PDF: ARCH
(2014)Objective
Aspirin plus clopidogrel versus warfarin in preventing vascular events in patients with ischemic stroke and aortic arch plaque ≥4 mm.
Study Summary
• Vascular death was significantly lower with DAPT (0% vs 3.4%; P=0.013), though trial was severely underpowered (349 of planned 744+ patients) and results are hypothesis-generating only.
Intervention
Aspirin 75–150 mg daily + clopidogrel 75 mg daily vs. warfarin adjusted to INR 2–3. Median follow-up was 3.4 years.
Study Design
Arms: Array
Outcome
• Vascular death — 0% (A+C) vs. 3.4% (warfarin); p=0.013
• Major hemorrhage — 2.3% vs. 3.4%; p=NS
• Intracranial hemorrhage — 2 patients (A+C), 1 fatal (warfarin)
• Total death — 4.7% (A+C) vs. 8.4% (warfarin); adjusted p=0.3
• Net benefit (primary outcome or major hemorrhage) — 9.9% vs. 13.6%; p=0.5
Bottom Line
Aspirin + clopidogrel did not significantly reduce the composite primary endpoint vs warfarin (7.6% vs 11.3%; adjusted HR 0.76; 95% CI 0.36-1.61; P=0.5) after median 3.4 years. Vascular death was significantly lower with DAPT (0% vs 3.4%; P=0.013), though trial was severely underpowered (349 of planned 744+ patients) and results are hypothesis-generating only.
Major Points
- Primary endpoint not different: 7.6% (DAPT) vs 11.3% (warfarin); adjusted HR 0.76 (95% CI 0.36-1.61; P=0.5).
- Vascular death: 0% (DAPT) vs 3.4% (warfarin); log-rank P=0.013 — only significant endpoint, but likely chance given underpowering.
- Severely underpowered: only 349 of planned 744+ patients; only 33 of required ≥70 primary events. Stopped for exhausted funding after 8+ years.
- Observed event rate far lower than expected: 3.5%/year vs expected 12%/year — modern secondary prevention dramatically reduced risk.
- On-treatment LDL reduced ~40 mg/dL, SBP ~130 mmHg in both arms — aggressive background therapy.
- Major hemorrhage similar: 2.3% (DAPT) vs 3.4% (warfarin); P=0.17.
- Warfarin TTR 67% (INR 2-3), 76% (INR 1.8-3.2). Trend: DAPT better at low TTR, warfarin better at high TTR.
- Aortic arch plaque ≥4mm diagnosed by TEE. 65-66% qualifying event was ischemic stroke, 31-33% TIA.
- High cardiovascular risk: 66% smokers, 73% hypertension, 67% hyperlipidemia.
- Authors suggest DAPT may be preferred given simpler monitoring, no INR requirement. Future trials should compare antiplatelet vs DOACs.
Study Design
- Study Type
- Prospective randomized controlled superiority trial (PROBE design)
- Randomization
- Yes
- Blinding
- Open-label treatment; blinded endpoint evaluation. 1:1 computer-based randomization.
- Sample Size
- 349
- Follow-up
- Median 3.4 years (range 1-8 years)
- Centers
- 40
- Countries
- France, Australia, Switzerland
Primary Outcome
Definition: Composite: ischemic stroke, MI, peripheral embolism, vascular death, or intracranial hemorrhage
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 20/177 (11.3%); 3.49/100 py | 13/172 (7.6%); 2.17/100 py | - (0.36-1.61) | 0.5 |
Limitations & Criticisms
- Severely underpowered: 349/744+ patients, 33/70+ events needed. Stopped for funding exhaustion.
- Open-label treatment (PROBE design).
- Event rate 3.5%/year vs expected 12%/year — designed on outdated 1996 estimates.
- Baseline imbalance in prior MI (8% vs 17.3%).
- No aspirin monotherapy arm.
- 8+ year enrollment — guidelines evolved significantly.
- No NOAC comparator (designed pre-NOAC era).
- Limited geography (France, Australia, Switzerland).
Citation
Stroke. 2014;45:1248-1257.